The objective of this research proposal is to characterize structurally certain blood clotting proteins and their precursors, and to seek a molecular basis for their function in coagulation and fibrinolysis. These studies should provide greater insight into the role of these clotting factors in normal blood coagulation as well as in abnormal states of hemostasis and, in particular, thrombosis formation. More specifically, it is intended to focus attention on four areas, namely: (1) a detailed analysis of the structural changes occurring in human fibrinogen and fibrin during the formation of insoluble, crosslinked fibrin and after partial and complete digestion by human plasmin; (2) the study of the similarities in amino acid sequence of the amino-terminal portions of the plasma and platelet fibrin-stabilizing factors (FSF); in addition, efforts will be made to define the structural defect in non-functional plasma FSF from a patient with a congenital absence of FSF activity; (3) the biochemical characterization of normal and non-functional, hemophilic human factor VIII (antihemophilic factor); moreover, it is hoped that the structural changes which occur in normal factor VIII during its interaction with other clotting proteins such as factor IX, thrombin, fibrin-stabilizing factor or plasmin can be defined; and (4) a comparative study of the structural-functional relationships of human, chimpanzee, rhesus monkey and baboon plasminogen will be done in an attempt to learn the significance of functional differences which exist among the four species of plasminogen.